Objective: Andrographolide was found to show moderate antimalarial activity against chloroquine-resistant strain of Plasmodium falciparum (PF). It thus becomes an interesting lead for new antimalarial drugs. This study describes a molecular docking of andrographolide and its derivative into the best PF geranylgeranyl pyrophosphate synthase (PFGGPPS) model. Methods:A comparative modeling of PFGGPPS based on a crystal structure of Plasmodium vivax GGPPS was optimized and conducted. This model was considered suitable for molecular docking. Partition coefficient of andrographolide was determined to assist its derivative design based on hydrophobicity property. Synthesis of the antimalarial drug was scaled up to 5 mm and identified by 13 C-and 1 H-nuclear magnetic resonance (NMR) spectroscopy. Results:The optimal comparative modeling of PFGGPPS was conducted on chain B (3PH7 chain B). The calculated coefficient partition of andrographolide's derivative was higher (+1.89), compared to that of andrographolide of +1.62. The NMR data of second and third synthesis experiments were consistent at the 5-mmol scale. Conclusions:On the molecular docking of andrographolide into the model, an antimalarial andrographolide derivative design that is more hydrophobic than andrographolide was proposed since the stronger hydrophobicity property of drug, the better of its activity of the drug. Synthesis of this derivative with a simple and green procedure was found to be reproducible.
Objective: Andrographolide is a major secondary metabolite in the Indonesian herb sambiloto (Andrographis paniculata). It displays a moderate antiplasmodial activity against the chloroquine-resistant strain of Plasmodium falciparum. This study aimed to investigate andrographolide inhibition of geranylgeranyl pyrophosphate synthase (GGPPS) by andrographolide molecular docking.Methods: A comparative modeling of P. falciparum GGPPS was conducted using one of the Plasmodium vivax GGPPS crystal structures as a template. The best model from this comparative modeling was then used in a molecular docking to investigate the binding mode of andrographolide in the P. falciparum GGPPS active site. Results:In the P. falciparum GGPPS active site, andrographolide is situated with its double rings pointing toward the hydrophobic pocket, while its lactone group is positioned between first aspartate-rich motif and second aspartate-rich motif of the catalytic pocket. Conclusions:In the active site, andrographolide is situated with its double rings pointing toward the hydrophobic pocket, while its lactone group is positioned in the catalytic pocket.
Ethyl p-methoxycinnamate (EPMC) (1) is a major natural ester found in the rhizome of Kaempferia galanga and has been reported to have anti-inflammatory activity. Some of the structural modification of this compound has been carried out in order to study the structure-activity relationship on its anti-inflammatory activity. In the present study, we report a new, simple and efficient procedure in the conversion of the ethyl p-methoxycinnamate into N,N-dimethyl-p-methoxycinnamamide (5) and then study the structure-activity relationship on its anti-inflammatory activity. The reaction was carried out through a microwave-assisted direct amidation between (EPMC) (1) with dimethylformamide (DMF) in the basic condition. The mixture was irradiated by using unmodified microwave-oven at 300 W for 1 minute to obtain compound (5) in 88.8% yields. The extensive analysis of the GCMS and NMR data supported that the product of synthesis is N,N-dimethyl-p-methoxycinnamamide (5). Evaluation of the anti-inflammatory activity of compound 5 by using anti-denaturation of heat bovine serum albumin (BSA) assay indicated that N,N-dimethyl-p-methoxycinnamamide (5) still have anti-denaturation activity. Compound 5 has an amide functional group which is more slowly hydrolyzed if compared to 1. Hence, the reaction has successfully produced a more stable compound which still has anti-inflammatory activity
Geraniol is a very valuable aroma chemical and has commonly been used in fragrances and aroma compound. Geraniol biotransformation by Aspergillus niger has been studied. The main bioconversion products obtained from geraniol and liquid culture of A. niger are linalool and alpha-terpineol. Linalool plays a major role in anti-inflammatory, antibacterial and antioxidant activities. This study aims to know the interaction of geraniol in Aspergillus niger enzyme with docking molecular. Comparative modeling of Aspergillus niger enzyme was conducted by means of one of the crystal structure of Linalool Dehydratase – Idomerase (LDI) as a template. The best model of this comparative modeling was then used in docking molecular to investigate geraniol binding mode inactive site enzyme of Aspergillus niger. Inactive site enzyme of Aspergillus niger, geraniol is located with hydrophobic and hydrogen bonds: Amino acid – the amino acids are Asn 105, Arg 96, Lys 112 inactive site - OH with hydrogen bond, Arg 97 inactive site – CH3 with hydrophobic bond and Leu54 inactive site – CH3 with the hydrophobic bond. The distances among pharmacophore respectively are 3,603 A, 6,768 A, and 7,345A. It has higher score (ΔGbind: -3.4 kcal/mol) compared to linalool (ΔGbind: -3.6 kcal/mol). Virtual tethering of linalool with LDI Aspergillus niger enzyme in amino acid Leu120 and Glu118 had been done. The pharmacophore is - OH and methyl C8 group. The distances among pharmacophore respectively are 5,835 Å, 2,52 Å, and 5,32 Å. Virtual tethering of LDI Aspergillus niger enzyme with geraniol has a higher score (ΔGbind: -3.4 kcal/mol) compared to linalool (ΔGbind: -3.6 kcal/mol). It shows that interaction between linalool and LDI Aspergillus niger enzyme is easier to occur than the interaction between geraniol and LDI Aspergillus niger enzyme, geraniol reaction to linalool that occurs is rearrangement reaction.
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